Beyond weight loss: Preserving muscle health in the incretin era

Incretin-based therapies have transformed the treatment of type 2 diabetes and obesity. 1 As the field has evolved from glucagon-like peptide-1 (GLP-1) receptor agonists to the glucose-dependent insulinotropic polypeptide (GIP)/ GLP-1 receptor agonist tirzepatide and, more recently, highly potent multi-agonists, the clinical challenge has begun to shift.The question is no longer whether substantial weight loss can be achieved, but whether it can be achieved while preserving muscle health, particularly in older adults.Retatrutide, an investigational triple GIP/GLP-1/glucagon receptor agonist, exemplifies this therapeutic progress.In a phase 2 body-composition sub-study involving people with type 2 diabetes, pooled 8-mg retatrutide regimens reduced body weight by approximately 16.8 kg over 36 weeks, compared with 2.1 kg with placebo and 0.8 kg with dulaglutide 1.5 mg. 2 Dual-energy X-ray absorptiometry (DXA) demonstrated an accompanying reduction of approximately 6.5 kg in lean mass, while most of the remaining weight loss reflected reductions in fat mass (Figure 1).This Commentary argues that the next challenge in the incretin era is not simply greater weight loss, but healthier weight loss-maximizing fat loss while preserving muscle health, particularly in older adults with type 2 diabetes.